Malformations and Developmental Disorders
 (+) genetic and environmental influences (toxins,
infections)
I. Neural Tube Defects
o Midline malformations involving some
combination of neural tissue, meninges, and
overlying bone or soft tissue
o Collectively the most common CNS malformations
o Pathogenic Mechanisms
 Failure of neural tube closure: secondary
mesenchymal tissue defects stem from
aberrant skeletal modeling around the
malformed tube
- Anencephaly
- Myelomeningocele
 Primary bone defects caused by abnormal
axial mesoderm development: lead to
secondary CNS abnormalities
- Encephalocele
- Meningocele
- Spina bifida
o Morphology
 Anencephaly
- Malformation of the anterior end of the
neural tube
- Absence of most of the brain and
calvarium
- Forebrain development disrupted at ~ 28
days of gestation; remnant in its place is
the area cerebrovasculosa (flattened
disorganized brain tissue with admixed
ependyma, choroid plexus, and
meningothelial cells)
- Posterior fossa structures may be spared
depending on extent of skull deficit
- Descending tracts associated with
disrupted structures are absent
 Myelomeningocele
- Extension of CNS tissue through a
vertebral column defect
- MC at lumbosacral region
- (+) LE motor and sensory deficits, B&B
dysfunction
- Complicated by superimposed infection
of the cord d/t defective function of the
thin overlying skin
 Encephalocele
- Extrusion of malformed brain tissue
through a midline defect in the cranium
- MC in the occiput
- Nasofrontal variants involving the orbit,
ethmoid, or cribriform plate (“nasal
glioma”) are also seen
 Spinal dysraphism or spina bifida
- MC NTD
- Asymptomatic (occulta) or severe
(flattened disorganized segment of spinal
cord associated with an overlying
meningeal outpouching)
o Clinical Features
 Frequency varies among ethnic groups (d/t
polymorphisms in enzymes involved in folic
acid metabolism)
 Overall recurrence rate for NTD in subsequent
pregnancies: 4-5%
 Folate deficiency during the first several
weeks of gestation – risk factor
- Folate supplementation can decrease
NTD risk but because neural tube closure
is normally complete by day 28 of
embryonic development (before most
pregnancies are recognized), it must be
given to women throughout their
reproductive years to be fully effective
- May be due to effects on DNA
methylation
II. Forebrain Anomalies
o Focal / diffuse
o Abnormalities in the generation and migration of
neurons
o The pool of proliferating precursor cells in the
developing brain lies in the germinal matrix
adjacent to the ventricular system
 Total number of neurons – determined by the
fraction of proliferating cells undergoing
transition into migrating cells with each cell
cycle
o Paths of migration from the germinal matrix to
the cerebral cortex:
Migration Progenitor Cell Destiny
Radial Excitatory neurons
Tangential Inhibitory interneurons
o Pattern depends on gene mutation
o Changes either in complexity of brain surface,
organization into lobes, cortical structure, or
neuronal distribution
 Brain volume changes: megalencephaly or
microencephaly

Microencephaly
- More common
- Typically with small HC
- Associated with chromosome
abnormalities, fetal alcohol syndrome,
and viral infection acquired in utero (HIV-
1, Zika virus)
- Reduction in the number of neurons that
reach the neocortex → simplification of
gyral folding
 Lissencephaly
- Reduction in the number of gyri
- Extreme form: no gyri (agyria)
- Types
1  Smooth surface form
 Mutations disrupting cell
migration (e.g. in cytoskeletal
motor proteins that drive
migration of neuroblasts)
2  Cobblestone surface form
 Genetic alterations that
disrupt the stop signal for
migration (depends on a set of
glycosylated proteins) – MC
mutations in enzymes that
place sugars onto these
proteins
 Polymicrogyria
- Numerous small irregularly formed
cerebral convolutions with shallow sulci
- Cerebral cortex composed of 4 or fewer
layers with fusion of the molecular layers
between gyri
- Can be induced by localized tissue injury
toward the end of neuronal migration
- Some are genetically determined
(typically bilateral and symmetric)
 Neuronal heterotopia
- Group of migrational disorders defined by
collections of subcortical neurons in
inappropriate locations along the
pathway of migration
- May be along the ventricular surface (no
migration at all)
- Periventricular nodular heterotopias –
can be caused by mutations in the gene
encoding filamin A (actin-binding protein
responsible for assembly of complex
meshwork of filaments) located in
chromosome X (mutant allele causes
male lethality; inn females, the process of
X inactivation separates neurons into
those with a normal allele and those with
the mutant allele)
- Doublecortin (DCX) – also in chromosome
X; mutation results in lissencephaly in
males and subcortical bandlike
heterotopias in females (parallel layer of
gray matter – “double cortex”)
 Holoprosencephaly
- Incomplete separation of the cerebral
hemispheres across the midline
- Severe forms with facial abnormalities
(e.g. cyclopia); intrauterine Dx now
possible
- Less severe variants (arrhinencephaly) –
absence of CN1 and related structures
- Associated with trisomy 13 or mutations
in genes encoding sonic hedgehog
signaling pathway components
 Agenesis of the corpus callosum
- Common
- Absence of interhemispheric white matter
bundles
- Radiology: misshapen lateral ventricles
(bat wing deformity); on coronal whole
mount sections of the brain, Probst
bundles of AP-oriented white matter can
be demonstrated
- Sometimes associated with intellectual
disability but may also be found in normal
individuals
- Sporadic/familial
- In isolation or associated with other
malformations
III. Posterior Fossa Anomalies
o Primarily affect the brainstem and cerebellum +/-
morphologic changes in other brain regions
o Morphology
 Arnold Chiari Malformation (Chiari type II)
- Small posterior fossa
- Misshapen midline cerebellum with
downward extension of the vermis
through the foramen magnum
- Hydrocephalus
- Lumbar myelomeningocele
- Other changes: medullary caudal
displacement, tectal malformation,
 aqueductal stenosis, cerebral
heterotopia, hydromyelia
 Chiari Type I Malformation
- Less severe
- Low lying cerebellar tonsils extend down
into the vertebral canal
- Silent or symptomatic if with impaired
CSF flow and medullary compression
(correctable with neurosurgery)
 Dandy Walker Malformation
- Enlarged posterior fossa
- Cerebellar vermis absent or present in
rudimentary form anteriorly; replaced by
a large midline cyst lined by ependyma
and contiguous with leptomeninges on its
outer surface
- The cyst represents the expanded roofless
4th ventricle in the absence of a normally-
formed vermis
- Commonly associated with dysplasia of
brainstem nuclei
 Joubert Syndrome
- Hypoplasia of the cerebellar vermis with
apparent elongation of the superior
cerebellar peduncles and an altered
brainstem shape – molar tooth sign on
imaging
- Mutations in genes encoding components
of the primary / nonmotile cilium
IV. Syringomyelia and Hydromyelia
o Hydromyelia - expansion of the ependyma-lined
central canal of the spinal cord
o Syringomyelia / syrinx – formation of a fluid-filled
cleft-like cavity inn the inner portion of the cord
 Syringobulbia – (+) brainstem extension
 May be associated with a Chiari
malformation, intraspinal tumors, or trauma
 Histology
- Destruction of the adjacent gray and
white matter surrounded by dense
reactive gliosis
 Manifests at 2nd/3rd decade of life
 s/sx: isolated loss of pain and temperature
sensation in the UE
- d/t disruption of the crossing anterior
spinal commissural fibers
Cerebrovascular Disease
 Hypoxia and Ischemia
o Brain – 1-2% BW but receives 15% of resting CO
and accounts for 20% of O2 consumption
o CBF remains ~ constant over a wide range of BP
and ICP d/t vascular resistance autoregulation
o Ischemia → inappropriate release of excitatory AA
NTs (e.g. glutamate) → damage neurons by
allowing excessive Ca influx through NMDA-type
glutamate receptors (excitotoxicity)
o Focal Cerebral Ischemia
 Obstructive
 Collateral flow
- Circle of Willis
- Cortical-leptomeningeal anastomoses
(distal branches of ACA, MCA, and PCA)
- Little (if any) for the deep penetrating
vessels
 Embolism – MC affects the MCA (R = L)
- Cardiac mural thrombi
- Thromboemboli from arteries (MC
carotids)
- Paradoxical embolism (CHD)
- Cardiac surgery
- Tend to lodge where BVs branch / in
areas of preexisting luminal stenosis
- Shower embolization – fat embolization;
manifest as generalized cerebral
dysfunction with disturbances of higher
cortical function and consciousness, often
without localizing signs
- Widespread hemorrhagic lesions
involving white matter – characteristic of
embolization of bone marrow after
trauma
 Thrombotic occlusion
- MC caused by acute change of vulnerable
atherosclerotic plaques (as in CAD)
- MC at carotid bifurcation, MCA origin,
and either ends of the basilar artery
- Thrombi → progressive lumen narrowing,
anterograde extension, fragmentation,
and distal embolization
 Inflammatory processes
- Can lead to luminal narrowing
- Infectious vasculitis of small and large
vessels occur with syphilis and TB,
immunosuppression and opportunistic
infection
 - Non-infectious: PAN and other systemic
vasculitis, primary angiitis of the CNS
 Other
- Hypercoagulable states
- Dissecting aneurysm of extracranial
arteries in the neck
- Drug abuse (amphetamine, heroin,
cocaine)
o +/- secondary hemorrhage
 The brain has end-organ circulation with
limited collateral supply → occlusive brain
infarcts generally start as nonhemorrhagic
(pale/anemic)
 Secondary hemorrhage can occur from
ischemia-reperfusion injury after spontaneous
/ therapeutic dissolution / fragmentation of
the intravascular occlusive material
- Hemorrhagic transformation
- Develops if the causative ischemic event
lasts long enough to damage small BVs in
the affected area
- The resulting reperfusion hemorrhages
are largely petechial in nature, but may
be multiple or confluent
o Morphology
 Both gross and microscopic appearance
change with time
 Grossly, little change in appearance during
the 1st 6 h of irreversible injury
- By 48 h, the tissue becomes pale, soft,
and swollen; gray-white junction
indistinct
- 2-10 d, the brain becomes gelatinous and
friable; the previously ill-defined border
between normal and infarcted tissue
becomes more distinct as edema resolves
in the viable adjacent tissue
- 10d-3wk, tissue liquefies → fluid-filled
cavity that continues to expand until all of
the dead tissue can be removed
 Microscopic
1. Acute infarct
- After the 1st 6-12 h, neurons in the
affected area show eosinophilic neuronal
necrosis (increased eosinophilia of the
cytoplasm followed by nuclear pyknosis
and karyorrhexis – dead red neurons)
- (+) cytotoxic and vasogenic edema
- Loss of tinctorial characteristics of white
and gray matter structures
- Endothelial and glial cells (astrocytes
mainly) swell
- Myelinated fibers begin to disintegrate
- Up to 48 h, neutrophilic emigration
progressively increases and then falls off
2. Subacute / evolving infarct
- Phagocytic cells (circulating monocytes
and activated microglia) evident at 48-72
h and become the predominant cell type
in the ensuing 2-3 weeks
- Macrophages become stuffed with the
products of myelin breakdown or blood
and may persist in the lesion for months
to years
- Reactive astrocytes and newly formed
vessels can be seen at the lesion
periphery as early as 1 week after the
insult
- With liquefaction and phagocytosis,
astrocytes at the lesion edges
progressively enlarge, divide, and develop
a prominent network of cytoplasmic
extensions
3. Healed infarct
- After several months, the astrocytic
response recedes, leaving behind a dense
meshwork of glial fibers, new capillaries,
and perivascular CT
- In the cerebral cortex, the cavity is
separated from the meninges and
subarachnoid space by a gliotic layer of
tissue (from molecular layer); pia and
arachnoid unaffected
- Stages progress from out to in
 Hemorrhagic infarctions – additional blood
extravasation and resorption
- In individuals on anticoagulation, may be
associated with intracerebral hematomas
- Venous infarcts – often hemorrhagic and
may occur after thrombotic occlusion of
the superior sagittal sinus or deep
cerebral veins; venous thrombosis risk
increases with neoplasms, localized
infections, and hypercoagulable states
o Lacunar Infarcts (Lacunes)
 Hypertension affects the deep penetrating
arteries and arterioles supplying the BG,
 hemispheric white matter, and BS; develop
arteriolosclerosis (400-900um) → thrombosis
and occlusion → lacunar infarcts
 Small cavitary infarcts; lake-like spaces (<
15mm wide)
 Single / multiple
 Involve the putamen, GP, thalamus, internal
capsule, deep white matter, caudate nucleus,
and pons
 Microscopically, (+) tissue loss surrounded by
gliosis
 Clinically silent or severe, depending on
location
 Affected vessels may be associated with
widening of perivascular spaces without
tissue infarction (etat crible)
o Global Cerebral Ischemia / Hypoxia
 Generalized reduction in cerebral perfusion /
blood oxygen
 Reversible if mild (transient post-ischemic
confusional state); irreversible in some cases
(diffuse hypoxic/ischemic encephalopathy)
 Sensitivity to hypoxia: neurons > glial cells
- Oligodendrocytes and astrocytes are also
vulnerable
- Most sensitive neurons: pyramidal
neurons in the hippocampus (area CA1 –
Sommer sector), cerebellar Purkinje cells,
pyramidal neurons in the cerebral cortex
(layers III and IV)
 Widespread neuronal death; surviving
patients often in persistent vegetative state
 Others experience brain death
- Irreversible diffuse cortical injury
(isoelectric / flat EEG)
- BS damage
- Absent cerebral perfusion
- If maintained on mech vent, the brain
gradually undergoes widespread
liquefaction (“respirator brain”)
 Border zone / Watershed infarcts
- At areas in the most distal reaches of the
arterial blood supply
- MC at MCA-ACA – a few cm lateral to the
interhemispheric fissure; damage results
to a cortical wedge-shaped infarct with
secondary hemorrhagic transformation;
often bilateral
- Develop usually after severe hypotensive
episodes; MC in patients resuscitated
after cardiac arrest
Ꜫ
 Morphology
- Global ischemia – the brain becomes
edematous → widening of gyri, narrowing
of sulci
- Poor gray-white demarcation
- Distinction from focal ischemic injury
based on overall pattern of brain
involvement (not nature of cellular
pathology)
1. Early changes (6-12 h)
- Dead red neurons
- Acute changes later in astrocytes and
oligodendrocytes
2. Subacute changes (24 h – 2 weeks)
- Tissue necrosis, influx of macrophages,
vascular proliferation, and reactive gliosis
3. Repair (after 2 weeks)
- Removal of necrotic tissue, loss of normal
CNS architecture, and gliosis
- Laminar necrosis – pattern produced in
the cerebral neocortex; neuronal loss and
gliosis uneven (some layers preserved,
others destroyed)
 Intracranial Hemorrhage
Hemorrhage MC Associated With
Epidural Trauma
Subdural
Intraparenchymal Underlying CVD
Subarachnoid
o Intraparenchymal Hemorrhage
 Spontaneous/non-traumatic – MC in mid-late
adult life
 Types and their major causes
- Ganglionic (BG, thalamus) – hypertension
- lobar (cerebral hemispheres) – cerebral
amyloid angiopathy
 Contributory factors: systemic coagulation
disorders, neoplasms, vasculitis, aneurysms,
and vascular malformations
 Hypertension - MC associated with deep
hemorrhages (> 50% clinically significant, 15%
mortality)
- MC in the putamen; others include
thalamus, pons, cerebellar hemispheres
 - Arteriolar walls affected by hyaline
change are thickened but more prone to
rupture (most prominent in the BG and
subcortical white matter)
 Cerebral amyloid angiopathy (CAA)
- Amyloidogenic peptides deposited in the
walls of medium and small caliber
meningeal, cortical, and cerebellar vessels
- Involved vessels are rigid
- Hyaline consists of beta amyloid rather
than collagen
- Amyloid deposition weakens the vessel
wall → hemorrhage – (+) microbleeds
- Increased risk of bleed with the presence
of an Ꜫ2 or Ꜫ4 allele
- AD forms associated with APP mutations
– encodes precursor for A-beta peptides
 Cerebral AD arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL)
- Mutations in the NOTCH3 gene
- Recurrent small vessel infarct and
dementia
- Initially white matter changes
- MC presents at 35 y/o
 Morphology
- Acute primary intraparenchymal
hemorrhages – (+) central core of clotted
blood that compresses the adjacent
parenchyma → secondary infarction
(anoxic changes and edema)
- Edema resolves, hemosiderin and lipid
laden macrophages appear, and
proliferation of reactive astrocytes is seen
at the lesion periphery
- Old hemorrhages show areas of
parenchymal cavitary destruction with a
rim of brownish discoloration
 Clinical Features
- Devastating if large involvement or with
extension into the ventricular system
- If smaller regions are affected, may be
clinically silent or evolve like an infarct;
over weeks/months, hematoma is
gradually removed, +/- clinical
improvement
o Subarachnoid Hemorrhage
 Spontaneous MC d/t rupture of a saccular /
berry aneurysm in a cerebral artery
- Other causes: rupture of a primary
intracerebral hemorrhage into the
ventricular system, vascular
malformation, hematologic disturbances,
and tumors
 However, generally MC cause is trauma
 Saccular aneurysm – MC type of intracranial
aneurysm
- Other aneurysm types: atherosclerotic
(fusiform; MC at basilar artery), mycotic,
traumatic, and dissecting
- 90% near the major arterial branch points
in the anterior circulation
 Pathogenesis: Saccular aneurysms
- Absence of smooth muscle and intimal
elastic lamina – suggestive of being
developmental anomalies
- MC occur sporadically, but genetics are
considered; > risk in:
a. 1st degree relatives
b. Mendelian disorders – AD polycystic
kidney disease, Ehlers-Danlos
syndrome type IV, NF1, Marfan
Syndrome)
c. Fibromuscular dysplasia of
extracranial arteries
d. Coarctation of aorta
- Other predisposing factors: cigarette
smoking, hypertension
- Not present at birth (even if sometimes
referred to as congenital); develop over
time d/t an underlying media defect
 Morphology
- Unruptured saccular aneurysm – thin-
walled outpouching usually at an arterial
branch point along the circle of Willis or a
major vessel just beyond
- Few mm to 2-3 cm; bright red shiny
surface and a thin translucent wall
- Atheromatous plaques / calcifications /
thrombi may be found in the wall / lumen
of the aneurysm
- Evidence of prior hemorrhage: brownish
discoloration of the adjacent brain and
meninges
- Neck of aneurysm wide or narrow
- Rupture usually occurs at the apex of the
sac → extravasation of blood in the
subarachnoid space / parenchyma
 - Arterial wall adjacent to the aneurysm
neck – (+) intimal thickening and media
attenuation
- Smooth muscle and intimal elastic lamina
do not extend into the neck and are
absent from the aneurysm sac itself
(made up of thickened hyalinized intima
and a covering of adventitia)
 Clinical Features: rupture
- MC in the 5th decade, F > M
- Occur anytime but 1/3 cases associated
with acute increases in ICP, such as with
straining at stool or sexual orgasm
- Blood under arterial pressure is forced
into the subarachnoid space → sudden
excruciating HA
- 25-50% die with the first rupture; those
who survive often improve and recover
consciousness in minutes
- Repeat bleed common in survivors and
unpredictable in timing
- Clinical consequences of blood in the
subarachnoid space:
a. Acute (hours – days) – increased risk
of additional ischemic injury from
vasospasm affecting vessels bathed in
extravasated blood; most significant
in basal SAH (major vessels of the
circle of Willis can be involved);
mediators include endothelin, NO,
arachidonic acid metabolites
b. Late – associated with healing
processes; meningeal fibrosis and
scarring – may obstruct CSF flow
o Vascular Malformations
 Types: AVM, cavernous malformations,
capillary telangiectasias, venous angiomas
- 1st 2 associated with hemorrhage risk
 AVM frequently associated with activating
somatic mutations in the KRAS oncogene
within the endothelial cells that line the
malformed vessels (dysregulated RAS
signaling)
 Morphology
1. AVM
- Tangled networks of worm-like vascular
channels with high BF d/t prominent
pulsatile AV shunting
- Vessels involved: subarachnoid space /
brain parenchyma
- Composed of greatly enlarged BVs
separated by gliotic tissue, often with
evidence of prior hemorrhage
- Some are arteries with
duplication/fragmentation of the internal
elastic lamina, while others show marked
thickening or partial replacement of the
media by hyalinized CT
2. Cavernous malformations
- Distended loosely organized vascular
channels arranged back-to-back with
collagenized walls of variable thickness
- (-) brain parenchyma in between vessels
- MC in the cerebellum, pons, and
subcortical regions
- Low flow (no shunting)
- Foci of old hemorrhage, infarction, and
calcification frequently surround the
abnormal vessels
 Clinical Features: AVM
- M>F
- Often presents at 10-30 y/o as a seizure
d/o, an ICH, or a SAH
- MC at posterior branches of MCA
- Large AVM in the newborn can lead to
CHF d/t shunting, especially if the vein of
Galen is involved
**cavernous malformations – familial forms
common (hallmark: multiple lesions;
penetrant AD)
 Vascular Dementia
o Individuals who suffer multiple bilateral gray
(cortex, thalamus, BG) and white (centrum
semiovale) matter infarcts over months-years
may develop a distinct clinical syndrome of:
 Dementia
 Gait abnormalities
 Pseudobulbar signs with FND
o d/t multifocal vascular disease
 Cerebral atherosclerosis
 Vessel thrombosis / embolization from
carotid vessels or the heart
 Cerebral arteriolosclerosis from chronic
hypertension
o Binswanger disease – injury pattern preferentially
involves large areas of the subcortical white
 matter with myelin and axon loss (subcortical  In immunosuppressed individuals, purulent
white matter dementia) meningitis may be caused by other infectious
organisms such as Klebsiella or anaerobes –
atypical clinical course and CSF findings
 Morphology
- Exudate evident within the
leptomeninges over the brain surface
- Meningeal vessels engorged and
CNS INFECTIONS prominent
 Infections may damage the nervous system directly - H. influenza meningitis – basal;
by the infectious agent or indirectly by microbial Pneumococcal meningitis – densest over
toxin, inflammatory responses, and immune- cerebral convexities near the sagittal
mediated mechanisms sinus
 Routes of microbe entry - From areas of greatest accumulation,
o Hematogenous – MC; often via arterial tracts of pus follow along BVs on the brain
circulation; venous spread occurs retrograde via surface
anastomoses with facial veins - If fulminant, +/- ventriculitis; lack of BBB
o Direct inoculation – traumatic or may be in the choroid plexus may also be the
associated with congenital malformations such as portal for CSF involvement of blood-borne
meningomyelocele infections
o Local extension – air sinuses, teeth, skull, - Neutrophils fill the subarachnoid space in
vertebrae severely affected areas; predominant
o PNS – viral spread like with rabies and herpes around leptomeningeal BVs in < severe
zoster cases
I. Acute Meningitis - In fulminant meningitis, the inflammatory
 Acute pyogenic – bacterial cells infiltrate the walls of the
 Aseptic – acute/subacute viral leptomeningeal veins and may extend
 Chronic – tuberculous, spirochetal, into the brain substance (cerebritis)
cryptococcal - Secondary vasculitis and venous
1. Acute Pyogenic (Bacterial) Meningitis thrombosis may lead to hemorrhagic
 E. coli and GBS – neonates cerebral infarction
 S. pneumoniae and L. monocytogenes – - Leptomeningeal fibrosis may follow
elderly pyogenic meningitis and cause
 N. meningitidis – adolescents and young hydrocephalus; in pneumococcal
adults meningitis, large quantities of the
 Systemic signs of infection superimposed on capsular polysaccharide of the organism
symptoms related to meningeal irritation and produce a gelatinous exudate that
neurologic impairment promotes arachnoid fibrosis (chronic
 CSF: 90,000 neutrophils per mm 3, increased adhesive arachnoiditis)
CSF pressure, increased protein, reduced 2. Acute Aseptic (Viral) Meningitis
glucose  (-) bacterial culture but with s/sx of meningitis
 Fatal if untreated  Generally viral but may be bacterial /
 Complication: Waterhouse-Frederichsen rickettsial / autoimmune
Syndrome  Less fulminant clinical course
- Results from meningitis associated  CSF: lymphocytic pleocytosis, moderate
septicemia and hemorrhagic infarction of protein increase, glucose ~ normal
the adrenal glands  Self-limited; symptomatic tx; etiology rarely
- MC with meningococcal and identified – MC enteroviruses (80%)
pneumococcal meningitis
  Clinical picture may develop after rupture of  Bacterial (and rarely fungal) infections of the
an epidermoid cyst into the subarachnoid skull bones or air sinuses can spread to the
space or with chemical meningitis subdural space
- CSF: sterile, pleocytosis with neutrophils,  +/- mass effect and/or thrombophlebitis of
increased protein, normal glucose the bridging veins – can cause occlusion and
II. Acute Focal Suppurative Infections infarction of the brain
o Pyogenic bacteria / fungi  FNDs, febrile, HA, neck stiffness
1. Brain Abscess  CSF profile similar to that of brain abscess
 Localized focus of necrosis of brain tissue with  Full recovery with prompt Dx and Tx; only
accompanying inflammation, MC because of residuum is a thickened dura
bacterial infection 3. Extradural Abscess
 Causes  Commonly associated with osteomyelitis
- Direct implantation  MC from an adjacent focus of infection
- Local extension (mastoiditis, paranasal (sinusitis) or post-op
sinusitis)  If at the spinal epidural space, it may cause
- Hematogenous spread (heart, lungs, SCC – neurosurgical emergency
bone; bacteremia from dental III. Chronic Bacterial Meningoencephalitis
procedures) o Causes: Mycobacterium tuberculosis, Treponema
 Predisposing conditions pallidum, and Borrelia
- Acute bacterial endocarditis 1. Tuberculosis
- CHD with R to L shunting and loss of  May be part of active disease elsewhere in
pulmonary filtration the body or appear in isolation after seeding
- Chronic pulmonary sepsis (bronchiectasis) from silent lesions (MC from lungs)
- Systemic disease with  May involve the meninges or the brain itself
immunosuppression  Morphology
 MC organisms in non-immunosuppressed a. Diffuse meningoencephalitis
patients: streptococci and staphylococci - MC pattern
 Morphology - Subarachnoid space contains a
- Discrete lesions with central liquefactive gelatinous / fibrinous exudate
necrosis surrounded by brain swelling characteristically involving the base of the
- (+) exuberant granulation tissue with brain, effacing the cisterns and encasing
neovascularization – newly formed cranial nerves
vessels are abnormally permeable → - +/- discrete white areas of inflammation
marked vasogenic edema scattered over the leptomeninges
- In well-established lesions, a collagenous - Involved areas contain a mixed
capsule is produced by fibroblasts from inflammatory infiltrate with lymphocytes,
BV walls; outside the fibrous capsule is a plasma cells, and macrophages
zone of reactive gliosis with numerous - Florid cases show well-formed
gemistocytic astrocytes granulomas with caseous necrosis and
 Clinical Features giant cells
- Progressive FNDs; s/sx related to - Arteries running through the
increased ICP subarachnoid space may show
- CSF: high WBC count, increased protein obliterative endarteritis and marked
concentration, normal glucose intimal thickening
- Complications: herniation, rupture with - May spread to the choroid plexus and
ventriculitis / meningitis, venous sinus ependymal surface, travelling through the
thrombosis CSF
- Low mortality with proper tx
2. Subdural Empyema
 - In long-standing cases, a dense fibrous
adhesive arachnoiditis may develop (most
conspicuous around the brain base)
- +/- hydrocephalus
b. Tuberculoma
- Well-circumscribed intraparenchymal
mass, +/- meningitis
- If several cm in diameter, may cause
significant mass effect
- (+) central caseous necrosis
- Calcified if inactive
 Clinical Features
- HA, malaise, mental confusion, vomiting
- CSF: pleocytosis made up of mononuclear
cells +/I neutrophils, increased protein,
moderately decreased / normal glucose
- Most serious complications of chronic
tuberculous meningitis:
a. Arachnoid fibrosis → hydrocephalus
b. Obliterative endarteritis → arterial
occlusion and brain infarction
- If the spinal cord subarachnoid space is
involved, nerve roots may be affected
- Tuberculomas – d/dx: CNS tumors
- < host reaction in AIDS patients
2. Neurosyphilis
 Manifestation of the tertiary stage of syphilis
 Occurs in 10% individuals with untreated
infection
 Patterns: meningovascular / paretic / tabes
dorsalis
 d/t impaired cell-mediated immunity, > risk in
patients with HIV (especially acute syphilitic
meningitis or meningovascular disease)
 Morphology
1. Meningovascular neurosyphilis
- Chronic meningitis involving the base of
the brain, the cerebral convexities, and
spinal leptomeninges
- +/- obliterative endarteritis (Heubner
arteritis) with distinctive perivascular
inflammatory reaction rich in plasma cells
and lymphocytes
- Cerebral gummas (plasma cell – rich mass
lesions) may also occur in the meninges
and extend into the parenchyma
2. Paretic neurosyphilis
- Invasion of the brain by T. pallidum
- Insidious but progressive cognitive
impairment associated with mood
alterations (including delusions of
grandeur) that terminate in severe
dementia (general paresis of the insane)
- Parenchymal damage of the cerebral
cortex – common in the frontal lobe
- Loss of neurons, proliferation of
microglia, gliosis, and iron deposits
(Prussian blue stain)
- Spirochetes in tissue sections
3. Tabes dorsalis
- Damage to sensory axons in the dorsal
roots
- Impaired joint position sense, locomotor
ataxia
- Loss of pain sensation → Charcot joint
- Lightning pain, areflexia
- Loss of both axons and myelin in the
dorsal roots, with pallor and atrophy in
the dorsal columns of the SC
- Organisms not demonstratable
3. Neuroborreliosis (Lyme Disease)
 Caused by the spirochete Borrelia burgdorferi
(transmitted by Ixodes ticks)
 Neurologic symptoms highly variable: aseptic
meningitis, facial nerve palsies,
polyneuropathies, encephalopathy
 Focal proliferation of microglial cells in the
brain; scatted extracellular organisms
IV. Viral Meningoencephalitis
o Some viruses have a propensity to infect the
nervous system (cell type or brain area)
o Consider latency
o Systemic viral infections in the absence of direct
evidence of viral penetration into the CNS may be
followed by an immune-mediated disease (e.g.
perivenous demyelination)
1) Arthropod-borne
 Arboviruses – important cause of epidemic
encephalitis; animal hosts, insect vectors
 Neurologic deficits: generalized (seizures,
confusion, delirium, stupor/coma) and focal
 Involvement of the spinal cord in West Nile
encephalitis can lead to a polio-like syndrome
with paralysis
 CSF: colorless, slightly increased pressure,
increased protein, normal glucose;
neutrophilic pleocytosis → lymphocytosis
  Morphology  In utero infection → periventricular necrosis
- Perivascular accumulation of lymphocytes → severe brain destruction → microcephaly
+/- neutrophils and periventricular calcification
- Multiple foci of necrosis of gray and white  Morphology (immunosuppressed)
matter - Subacute encephalitis +/- CMV inclusion-
- Single cell neuronal necrosis with bearing cells
phagocytosis of the debris - Localize in the subependymal regions →
(neuronophagia) severe hemorrhagic necrotizing
- Microglial cells form small aggregates: ventriculoencephalitis and choroid plexitis
microglial nodules - Can also attack the lower SC and roots →
- Severe cases: necrotizing vasculitis with radiculoneuritis
focal hemorrhages - May affect any CNS cell
2) Herpes Simplex Virus Type 1 - Infection confirmed with
 Encephalitis MC in children and young adults; immunohistochemistry
10% have a history of prior herpetic infection - Conventional light microscopy: prominent
 Typical presenting sx: changes in mood, enlarged cells with intranuclear and
memory, and behavior intracytoplasmic inclusions
 Effectively treated with antivirals 6) Poliomyelitis
 Morphology  In non-immunized individuals, poliovirus
- Starts in and most severe at the inferior infection causes subclinical / mild
and medial temporal lobes and the orbital gastroenteritis but rarely can secondarily
gyri of the frontal lobes invade the nervous system
- Necrotizing and hemorrhagic  Morphology
- Perivascular inflammatory infiltrates - Acute cases show mononuclear cell
- Cowdry type A intranuclear viral perivascular cuffs and neuronophagia of
inclusions may be found in neurons and the AHCs (may extend posteriorly, +/-
glia cavitation)
- If slowly evolving, brain involvement is  Clinical Features
more diffuse - Initial: meningeal irritation and CSF
3) HSV Type 2 picture consistent with aseptic meningitis
 Adults: meningitis → +/- progression to involve the spinal
 Neonates: encephalitis – vaginal delivery in cord → flaccid paralysis (may involve the
women with active primary HSV genital respiratory muscles)
infections - Myocarditis can sometimes complicate
 HIV patients: acute hemorrhagic and the acute infection
necrotizing encephalitis - Postpolio syndrome can develop in
4) Varicella Zoster Virus patients 25-35 years after resolution of
 Primary infection (chickenpox) – childhood the initial illness; progressive weakness
exanthems without neurologic involvement with decreased muscle mass and pain;
 Reactivation in adults: shingles / herpes superimposed loss of remaining motor
zoster neurons without evidence of viral re-
- Self-limited but there may be activation
postherpetic neuralgia syndrome (after 60 7) Rabies
y/o) – vaccine preventable  Severe encephalitis
5) Cytomegalovirus  From a bite of a rabid animal; exposure to
 In fetuses and immunosuppressed individuals certain bat species without a bite can also
(common opportunistic infection in AIDS) cause it
 Morphology
 - External brain: intense edema and
vascular congestion
- Widespread neuronal degeneration and
inflammation most severe in the
brainstem
- BG, DC and DRG may be involved
- Negri bodies – pathognomonic;
cytoplasmic round/oval eosinophilic
inclusions in pyramidal neurons of the
hippocampus and Purkinje cells of the
cerebellum (sites of no inflammation);
viruses can be detected within by
ultrastructural and immunohistochemical
methods
 Clinical Features
- Virus enters the CNS by ascending along
peripheral nerves from the wound site
- Incubation period: 1-3 months
(depending on distance between wound
and brain)
- Disease begins with nonspecific
symptoms: malaise, HA, fever; if with
local paresthesia around the wound –
diagnostic
- As the infection advances, the affected
individual exhibits extraordinary CNS
excitability (slight touch is painful and
produces violent motor responses or
convulsions)
- Contracture of pharyngeal muscles on
swallowing → mouth foaming; aversion to
swallowing and water (hydrophobia)
- Meningeal irritation, flaccid paralysis
- Alternating periods of mania and stupor
progress to coma and eventual death
from respiratory failure
8) HIV
 Direct effects of the virus on the nervous
system, opportunistic infections, and primary
CNS lymphoma (EBV-positive B-cell tumor) –
decreased frequency d/t current effective
antiretroviral tx
 HIV aseptic meningitis – occurs in 1-2weeks of
seroconversion in 10% patients
- (+) HIV specific antibodies; virus can be
isolated from CSF
- Early phase: mild lymphocytic meningitis,
perivascular inflammation, myelin loss
- Among CNS cells, only microglia express
both CD4 and CCR5/CXCR4 receptors
- Chronic: HIV encephalitis
 Immune reconstitution Inflammatory
Syndrome (IRIS)
- Identified in some patients after effective
tx; paradoxical deterioration after starting
therapy
- Exuberant reconstituted inflammatory
response; intense inflammation with an
influx of CD8+ lymphocytes
 Morphology
- HIV encephalitis: chronic inflammatory
reaction associated with widely
distributed microglial nodules (contain
macrophage-derived multinucleated giant
cells)
- +/- foci of tissue necrosis and reactive
gliosis
- Some of the microglial nodules are found
near small BVs – abnormally prominent
endothelial cells and perivascular foamy /
pigment-laden macrophages
- Changes prominent in the subcortical
white matter, diencephalon, and
brainstem
- HIV can be detected CD4+ microglia and
mononuclear/multinucleated
macrophages
 Clinical Features
- Cognitive changes (mild or HIV-associated
dementia) – HIV-associated
neurocognitive disorders (HAND) – most
closely related to inflammatory activation
of microglial and perivascular
macrophages
- Mechanisms of neuronal dysfunction:
cytokine action, HIV-derived protein
toxicity, anti-HIV tx neurotoxicity,
accelerated aging, aberrant synaptic
pruning
9) Progressive Multifocal Leukoencephalopathy
 Encephalitis caused by the JC polyomavirus –
preferentially infects oligodendrocytes –
demyelination is the principal pathologic
effect
 Often exclusive in immunosuppressed
individuals (chronic lymphoproliferative /
myeloproliferative illnesses,
 immunosuppressive chemotherapy,
granulomatous diseases, AIDS)
 Most people have serologic evidence of
exposure to JC virus by 14 y/o, but primary
infection asymptomatic
 PML results from viral reactivation with
immunosuppression
 Clinically: affected individuals develop focal
and relentlessly progressive neurologic s/sx
 Imaging: extensive multifocal cerebral /
cerebellar white matter lesions
 Morphology
- Patches of irregular ill-defined white
matter injury ranging from mm to large
confluent lesions
- Area of demyelination MC in a subcortical
region; at the center are sheets of lipid-
laden macrophages and a reduced
number of axons
- Greatly enlarged oligodendrocyte nuclei
with glassy amphophilic viral inclusions –
immunohistochemistry; seen at lesion
edge
- Bizarre giant astrocytes with >1 irregular
hyperchromatic nuclei are intermixed
with more typical reactive astrocytes
- Infection of granule cell neurons in the
cerebellum – rare
V. Fungal Meningoencephalitis
o MC in immunocompromised individuals;
widespread hematogenous dissemination reaches
the brain
o MC: Candida, Mucor, Aspergillus, Cryptococcus
o Direct extension may also occur, especially in
mucormycosis with DM
o Forms of CNS fungal infection: chronic meningitis,
vasculitis, and parenchymal invasion
 Vasculitis – Mucormycosis and Aspergillosis
MC; vascular thrombosis can produce
hemorrhagic infarction
 Parenchymal invasion – MC as granulomas or
abscesses; Candida and Cryptococcus MC
- Candidiasis: multiple microabscesses +/-
granuloma formation
- Cryptococcus: parenchymal aggregates
typically found within expanded
perivascular (Virchow-Robin) spaces and
are associated with minimal/no
inflammation or gliosis
 Cryptococcal meningitis
- Common in AIDS
- May be fulminant and fatal in 2 weeks or
indolent (months/years)
- CSF may contain few cells but usually has
a high protein concentration
- Mucoid encapsulated yeasts can be
visualized in the CSF with special stains or
detected indirectly using assays for
cryptococcal antigens
- MC C. neoformans; other: C. gattii –
formation of cryptococcomas
VI. Other Infections of the Nervous System
o Protozoal diseases (malaria, toxoplasmosis,
amebiasis, trypanosomiasis), rickettsial infections
(typhus, Rocky Mountain spotted fever), and
metazoal diseases (cysticercosis, echinococcosis)
1) Cerebral toxoplasmosis
 Common opportunistic infection in HIV
 Subacute, evolves during a 1–2-week period
 Focal/diffuse
 CT / MR: multiple ring-enhancing lesions
- Non-specific; also in CNS lymphoma, TB,
and fungal infections
 In non-immunosuppressed, the impact of
toxoplasmosis is most often seen when
primary maternal infection occurs early in
pregnancy
- Spread to the brain of the developing
fetus and cause severe damage in the
form of multifocal necrotizing lesions that
may calcify
 Treatable with antibiotics with early dx
 (+) brain abscess – most often in the cerebral
cortex and deep gray nuclei
- Acute lesions: central necrosis, petechial
hemorrhages surrounded by acute and
chronic inflammation, macrophage
infiltration, and vascular proliferation
- Free tachyzoites and encysted bradyzoites
may be found at the periphery of the
necrotic foci
- Seen on routine H&E or Giemsa stains,
but more recognized with
immunohistochemical methods
- BVs near the lesions: intimal
proliferation / frank vasculitis with
fibrinoid necrosis or thrombosis
2) Cerebral amebiasis
  Rapidly fatal necrotizing encephalitis from
Naegleria species infection
 Chronic granulomatous meningoencephalitis
associated with Acanthamoeba
 Amebae – difficult to distinguish
morphologically from activated macrophages
 Methenamine silver or PAS can help in
visualization
3) Cerebral malaria
 Complication of infection by Plasmodium
falciparum
 Result of sticking of infected RBCs to the
inflamed vascular endothelium
 Reduced cerebral BF a
 Ataxia, seizures, and coma in the acute phase;
long term cognitive deficits in 20% children